Schizophrenia is a common and disabling psychotic disorder characterized by extreme disturbances of cognition and thought, affecting language, perception and sense of self. Despite the availability of a number of agents for the treatment of schizophrenia, it remains a significant burden on healthcare systems. Most of the antipsychotic drugs, although effective against psychosis, do not improve and may even exacerbate the negative symptoms of schizophrenia.
Paliperidone, an atypical antipsychotic, is an active metabolite of risperidone used for the treatment of schizophrenia and bipolar disorder. While its specific mechanism of action is unknown, it is believed that paliperidone and risperidone act via similar, if not the same, pathways.
Paliperidone, i.e, 9-hydroxyrisperidone, is chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and has the following structural formula (I).

U.S. Pat. No. 5,158,952 and its equivalent EP 368,388 disclose paliperidone, compositions comprising paliperidone and methods of its use. The synthetic process employed is depicted in the following scheme.
wherein the compound of formula (II) is reacted with the compound of formula (V) at 90° C. for 5 hours to yield the compound of formula (III) which is purified by column chromatography using trichloromethane and methanol and further recrystallized from isopropanol. The compound of formula (III) is further reduced to the compound of formula (IV) in methanol using a palladium on carbon as catalyst, which is further condensed with the compound of formula (VI) to yield paliperidone of formula (I).
The process disclosed in the U.S. Pat. No. 5,158,952 has several disadvantages. First, the intermediate (III) is obtained as an oily mass. This oily mass contains impurities which are difficult to separate by crystallization. In this process, a solid product is obtained only after purification by column chromatography thereby making the process non economical on an industrial scale. Second, hydrogenolysis of the compound of formula (III) to the compound of formula (IV) leads to undesirable dechlorination resulting in the des-chloro impurity of compound of formula (VII).

Paliperidone thus obtained by condensation of the compound of formula (IV) with the compound of formula (VI) is of poor quality and is further purified by column chromatography and solvent crystallizations, thereby making the process time consuming and expensive.
Therefore, there exists a need for a more economical and efficient method of making pure paliperidone which is suitable for industrial scale up.